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Blood, 15 January 2008, Vol. 111, No. 2, pp. 613-623.
Prepublished online as a Blood First Edition Paper on September 21, 2007; DOI 10.1182/blood-2007-06-098392.
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Submitted June 28, 2007
Accepted September 14, 2007
Thrombospondin-1 stimulates platelet aggregation by blocking the anti-thrombotic activity of nitric oxide/cGMP signaling
Jeff S Isenberg, Martin J Romeo, Christine Yu, Christine K Yu, Khauh Nghiem, Jude Monsale, Margaret E Rick, David A Wink, William A Frazier, and David D Roberts*
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
Hematology Service, Clinical Center, National Institutes of Health, Bethesda, MD, United States
Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO, United States
* Corresponding author; email: droberts{at}helix.nih.gov.
Platelet  -granules constitute the major rapidly releasable reservoir of thrombospondin-1 in higher animals. Although some fragments and peptides derived from thrombospondin-1 stimulate or inhibit platelet aggregation, its physiological function in platelets has remained elusive. We now show that endogenous thrombospondin-1 is necessary for platelet aggregation in vitro in the presence of physiological levels of nitric oxide (NO). Exogenous NO or elevation of cGMP delays thrombin-induced platelets aggregation under high shear and static conditions, and exogenous thrombospondin-1 reverses this delay. Thrombospondin-1 null murine platelets fail to aggregate in response to thrombin in the presence of exogenous NO or 8Br-cGMP. At physiological concentrations of the NO synthase substrate arginine, thrombospondin-1 null platelets have elevated basal cGMP. Ligation of CD36 or CD47 is sufficient to block NO-induced cGMP accumulation and mimic the effect of thrombospondin-1 on aggregation. Exogenous thrombospondin-1 also reverses the suppression by NO of IIb/ 3 integrin-mediated platelet adhesion on immobilized fibrinogen, mediated in part by increased GTP loading of Rap1. Thrombospondin-1 also inhibits cGMP-mediated activation of cGMP-dependent protein kinase and thereby prevents phosphorylation of VASP. Thus, release of thrombospondin-1 from -granules during platelet activation provides positive feedback to promote efficient aggregation by overcoming the anti-thrombotic activity of physiological NO.
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